Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH), is a hormone closely related to reproductive functions. When an exogenous LHRH or an analogue thereof is administrated with a physiological pulse frequency (once per 90 min) for a short period of time and at a small dose, it produces some promoting effects to the pituitary-gonadal system, and hence is used clinically for treating symptoms such as sexual dysfunction, anovulation, delayed puberty, etc. When it is administrated with a non-physiological pulse frequency for a long period of time and at a large dose, it can inhibit the hypophysis from secreting luteinizing hormone (LH) and follicle stimulating hormone (FSH), resulting in a decrease in the hormone secretion capacity of gonad and the atrophy of sexual organs. It is thus used clinically for treating some hormone-dependent diseases such as prostate cancer, hysteromyoma, breast carcinoma, adenomyosis, precocious puberty, etc.
Analogues of LHRH regulate the secretion of LH and FSH through feedback inhibition by competitively binding to most of the hypophyseal LHRH receptors, whereby inhibit the produce of ovarian estrogen, and achieve therapeutic effect of medical oophorectomy. Studies have shown that lives of prostate cancer patients can be prolonged by administering hormone analogues of LHRH (such as goserelin) after radiotherapy. Available information has shown that hormone analogues of LHRH are at least able to achieve the same therapeutic effect as surgical castration or CMF chemotherapy, and are used as postoperative adjuvant treatment for premenopausal patients with breast cancer; and achieve the same therapeutic effect as CMF chemotherapy in estrogen receptor-positive patients with axillary lymph node metastasis, with fewer side effects, and more acceptable to the patients. In recent years, goserelin has been used for control of clinical signs and symptoms of endometriosis and adenomyosis to prevent recurrence of endometriosis after surgery, all obtained good results. In addition, goserelin has also been used for endometrium thinning and treatment of uterine fibroids and other symptoms. Several clinical products of LHRH analogues have been commercially available. For example, the goserelin preparation, with the trade name of “Zoladex”, has been approved in France in 1987 and approved by FDA On Dec. 29, 1989. Its dosage form is an implant, with a monthly injection dose of 3.6 mg/vial. Adults are subcutaneously injected 3.6 mg once every 28-days at anterior abdominal. However, “for the subcutaneous injection of Zoladex at anterior abdominal, the stype is preloaded in a disposable syringe, and the syringe needle is equivalent in size to the size 16 puncture needle which is 30 mm long, therefore as compared with subcutaneous injection of common drugs, the degree of pain caused by injection of Zoladex is higher and bleeding caused by injection of Zoladex occurs more often.”—Journal of Modern Clinical Medical, July, 2008, Volume 6 (7).
According to the characteristics of administration of goserelin to its clinical indications, patients often require long-term administration. Thus, in order to improve patient compliance, goserelin has been developed into long-acting sustained release preparations. Compared with the implant preparations, injecting microsphere preparations to patients significantly reduces the patients' pain and bleeding. Several commercially available LHRH analogues microspheres, such as leuprolide microspheres, adopt this drug release pattern. However, studies have shown that when microspheres are prepared from goserelin to which no pre-treatment is subjected, the drug entrapment efficiency is low and the loss in the manufacturing process is high, resulting in increasing in production cost. Pharmacokinetic studies of the prepared microspheres in animals have shown that the bioavailability of goserelin is low, which makes the drug incapable of acting to its full effect.